Antiviral Research
Volume 90, Issue 1, April 2011, Pages 22-32
Yohichi Kumaki, Miles K.Wandersee, Aaron J.Smith, Yanchen Zhou, Graham Simmons, Nathan M.Nelson, Kevin W.Bailey, Zachary G. Vest, Joseph K.-K.Li, Paul Kay-SheungChan, Donald F. Smee, Dale L.Barnarda
Abstract
Urtica dioicaagglutinin (UDA) is a small plant monomeric lectin, 8.7kDa in size, with anN-acetylglucosamine specificity that inhibits viruses fromNidovirales in vitro. In the current study, we firstexamined the efficacy of UDA on the replication of different SARS-CoV strains in Vero 76 cells. UDA inhib-ited virus replication in a dose-dependent manner and reduced virus yields of the Urbani strain by 90% at1.1±0.4g/ml in Vero 76 cells. Then, UDA was tested for efficacy in a lethal SARS-CoV-infected BALB/cmouse model. BALB/c mice were infected with two LD50(575PFU) of virus for 4h before the mice weretreated intraperitoneally with UDA at 20, 10, 5 or 0mg/kg/day for 4 days. Treatment with UDA at 5mg/kgsignificantly protected the mice against a lethal infection with mouse-adapted SARS-CoV (p<0.001), butdid not significantly reduce virus lung titers. All virus-infected mice receiving UDA treatments were alsosignificantlyprotectedagainstweightloss(p<0.001).UDAalsoeffectivelyreducedlungpathologyscores.At day 6 after virus exposure, all groups of mice receiving UDA had much lower lung weights than didthe placebo-treated mice. Thus, our data suggest that UDA treatment of SARS infection in mice leads to asubstantial therapeutic effect that protects mice against death and weight loss. Furthermore, the mode ofaction of UDAin vitrowas further investigated using live SARS-CoV Urbani strain virus and retroviral par-ticles pseudotyped with SARS-CoV spike (S). UDA specifically inhibited the replication of live SARS-CoV orSARS-CoV pseudotyped virus when added just before, but not after, adsorption. These data suggested thatUDA likely inhibits SARS-CoV infection by targeting early stages of the replication cycle, namely, adsorp-tion or penetration. In addition, we demonstrated that UDA neutralizes the virus infectivity, presumablyby binding to the SARS-CoV spike (S) glycoprotein. Finally, the target molecule for the inhibition of virusreplication was partially characterized. When UDA was exposed toN-acetylglucosamine and then UDAwas added to cells just prior to adsorption, UDA did not inhibit the virus infection. These data supportthe conclusion that UDA might bind toN-acetylglucosamine-like residues present on the glycosylatedenvelope glycoproteins, thereby preventing virus attachment to cells.
Keywords:
BALB/c mouse, SARS-CoVUrtica, dioicaagglutinin (UDA)